US8853390B2 - Processes for preparing 1,2-substituted cyclopropyl derivatives - Google Patents
Processes for preparing 1,2-substituted cyclopropyl derivatives Download PDFInfo
- Publication number
- US8853390B2 US8853390B2 US13/232,751 US201113232751A US8853390B2 US 8853390 B2 US8853390 B2 US 8853390B2 US 201113232751 A US201113232751 A US 201113232751A US 8853390 B2 US8853390 B2 US 8853390B2
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- chiral
- amine
- hydrogen
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- alkyl
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
- C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
- C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D237/14—Oxygen atoms
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C211/00—Compounds containing amino groups bound to a carbon skeleton
- C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
- C07C211/16—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of a saturated carbon skeleton containing rings other than six-membered aromatic rings
- C07C211/17—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of a saturated carbon skeleton containing rings other than six-membered aromatic rings containing only non-condensed rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/57—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings
- C07C233/58—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/09—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid esters or lactones
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/41—Preparation of salts of carboxylic acids
- C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/42—Separation; Purification; Stabilisation; Use of additives
- C07C51/43—Separation; Purification; Stabilisation; Use of additives by change of the physical state, e.g. crystallisation
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C61/00—Compounds having carboxyl groups bound to carbon atoms of rings other than six-membered aromatic rings
- C07C61/16—Unsaturated compounds
- C07C61/40—Unsaturated compounds containing halogen
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
- C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
- C07C67/347—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by addition to unsaturated carbon-to-carbon bonds
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/06—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with radicals, containing only hydrogen and carbon atoms, attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/06—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by halogen atoms or nitro radicals
- C07D295/073—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by halogen atoms or nitro radicals with the ring nitrogen atoms and the substituents separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/10—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms
- C07D295/104—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms with the ring nitrogen atoms and the doubly bound oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
Definitions
- the present invention relates to processes for preparing chiral cyclopropyl amine derivatives and salts thereof; intermediates useful for the preparation of such compounds and salts; pharmaceutical compositions comprising the compounds and salts; and method of using such compositions.
- the cyclopropyl amine derivatives are useful for binding to histamine H 3 receptor sites and for providing therapeutic agents for histamine H 3 mediated disease.
- chiral 1,2-substituted cyclopropyl carboxylic acid and chiral 1,2-substituted cyclopropyl amide derivatives are intermediate compounds useful for the preparation of chiral cyclopropyl amine derivatives of a general formula:
- R 1 , R 2 , R 3 , R 3a , R 3b , R 4 , and R 5 are as defined below.
- Compounds of formula (II) are described in WO 2007150010, published on Dec. 27, 2007, corresponding to U.S. patent application Ser. No. 11/766,987, filed on Jun. 22, 2007, and U.S. patent application Ser. No. 11/956,816, filed on Dec. 14, 2007, each of which are all hereby incorporated by reference.
- the present invention offers a more efficient process to obtain chiral compounds of formula (II) via the chiral resolution of an aryl-cyclopropanecarboxylic acid with chiral amines.
- the chiral resolution step forms a diasteriomeric chiral salt, which is crystallized to obtain an enantiomerically pure salt.
- the enantiomerically pure arylcyclopropyl carboxylic acid is obtained upon breaking up the salt.
- the resulting enantiomerically pure cyclopropyl carboxylic acids can be reacted with various amines to form amides, which can be reduced to form chiral amine derivatives.
- the intermediate chiral amines can be further coupled with a desired aromatic or heteroaromatic reagent to provide compounds of formula (II).
- histamine H 3 receptor antagonists have been identified as histamine H 3 receptor antagonists.
- Various histamine H 3 receptor antagonists are currently in clinical development for treatment of disease.
- Diseases for which histamine H 3 receptor antagonists are under clinical study include, for example, schizophrenia, cognitive deficits of schizophrenia, Alzheimer's disease, narcolepsy, cataplexy, sleep disorder, hyperalgesia, allergic rhinitis, obesity, attention-deficit hyperactivity disorder, and dementia.
- histamine H 3 receptor ligands can demonstrate therapeutic effect are deficits in attention, diseases with deficits of memory or learning, cognitive deficits and dysfunction in psychiatric disorders, mild cognitive impairment, epilepsy, seizures, and asthma, motion sickness, dizziness, Meniere's disease, vestibular disorders, vertigo, diabetes, type II diabetes, Syndrome X, insulin resistance syndrome, metabolic syndrome, pain, including neuropathic pain, neuropathy, pathological sleepiness, jet lag, drug abuse, mood alteration, bipolar disorder, depression, obsessive compulsive disorder, Tourette's syndrome, Parkinson's disease, and medullary thyroid carcinoma, melanoma, and polycystic ovary syndrome.
- the present invention relates to a process for preparing chiral cyclopropyl amine derivatives of formula (II), as described herein.
- the present invention relates to a process for preparing the chiral salts of aryl-cyclopropanecarboxylic acid with a chiral amine.
- the present invention also is directed to the chiral compounds and salts thereof prepared by the process for preparing chiral salts described above.
- the present invention also is directed a chiral aryl-cyclopropanecarboxylic acid salt.
- the present invention also is directed to various intermediates useful for preparing chiral compounds of formula (II).
- compositions including pharmaceutical compositions
- compounds of formula (II) or a salt thereof that are prepared by the above processes.
- the present invention also is directed to methods of using the compositions of the invention.
- aryl as used herein means a monocyclic hydrocarbon aromatic ring system. Representative examples of aryl include, but are not limited to, phenyl.
- aryl groups of this invention are substituted with 0, 1, 2, 3, 4, or 5 substituents independently selected from acyl, acyloxy, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxyimino, alkoxysulfonyl, alkyl, alkylcarbonyl, alkylsulfonyl, alkynyl, amido, carboxy, cyano, cycloalkylcarbonyl, formyl, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, mercapto, nitro, thioalkoxy, NR A R B , and (NR A R B )sulfonyl.
- substituents independently selected from acyl, acyloxy, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxyimino, alkoxysul
- heteroaryl refers to an aromatic ring containing one or more heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a tautomer thereof. Such rings can be monocyclic or bicyclic as further described herein. Heteroaryl rings are connected to the parent molecular moiety.
- heteroaryl or “5- or 6-membered heteroaryl ring”, as used herein, refer to 5- or 6-membered aromatic rings containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a tautomer thereof.
- examples of such rings include, but are not limited to, a ring wherein one carbon is replaced with an O or S atom; one, two, or three N atoms arranged in a suitable manner to provide an aromatic ring; or a ring wherein two carbon atoms in the ring are replaced with one O or S atom and one N atom.
- Such rings can include, but are not limited to, a six-membered aromatic ring wherein one to four of the ring carbon atoms are replaced by nitrogen atoms, five-membered rings containing a sulfur, oxygen, or nitrogen in the ring; five membered rings containing one to four nitrogen atoms; and five membered rings containing an oxygen or sulfur and one to three nitrogen atoms.
- 5- to 6-membered heteroaryl rings include, but are not limited to, furyl, imidazolyl, isoxazolyl, isothiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, [1,2,3]thiadiazolyl, [1,2,3]oxadiazolyl, thiazolyl, thienyl, [1,2,3]triazinyl, [1,2,4]triazinyl, [1,3,5]triazinyl, [1,2,3]triazolyl, and [1,2,4]triazolyl.
- bicyclic heteroaryl or “8- to 12-membered bicyclic heteroaryl ring”, as used herein, refers to an 8-, 9-, 10-, 11-, or 12-membered bicyclic aromatic ring containing at least 3 double bonds, and wherein the atoms of the ring include one or more heteroatoms independently selected from oxygen, sulfur, and nitrogen.
- bicyclic heteroaryl rings include indolyl, benzothienyl, benzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzoisothiazolyl, benzoisoxazolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, pteridinyl, purinyl, naphthyridinyl, cinnolinyl, thieno[2,3-d]imidazole, thieno[3,2-b]pyridinyl, and pyrrolopyrimidinyl.
- Heteroaryl groups of the invention may be substituted with hydrogen, or optionally substituted with one or more substituents independently selected from acyl, acyloxy, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxyimino, alkoxysulfonyl, alkyl, alkylcarbonyl, alkylsulfonyl, amido, carboxy, cyano, cycloalkyl, fluoroalkoxy, formyl, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, mercapto, nitro, alkylthio, —NR A R B , and (NR A R B )carbonyl.
- substituents independently selected from acyl, acyloxy, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxyimino, alkoxy
- Monocyclic heteroaryl or 5- or 6-membered heteroaryl rings are substituted with 0, 1, 2, 3, 4, or 5 substituents.
- Bicyclic heteroaryl or 8- to 12-membered bicyclic heteroaryl rings are substituted with 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9 substituents.
- Heteroaryl groups of the present invention may be present as tautomers.
- heterocyclic ring and “heterocycle”, as used herein, refer to a 4- to 12-membered monocyclic or bicyclic ring containing one, two, three, four, or five heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur and also containing either at least one carbon atom attached to four other atoms or one carbon atom substituted with an oxo group and attached to two other atoms.
- Four- and five-membered rings may have zero or one double bond.
- Six-membered rings may have zero, one, or two double bonds.
- Seven- and eight-membered rings may have zero, one, two, or three double bonds.
- the non-aromatic heterocycle groups of the invention can be attached through a carbon atom or a nitrogen atom.
- the non-aromatic heterocycle groups may be present in tautomeric form.
- Representative examples of nitrogen-containing heterocycles include, but are not limited to, azepanyl, azetidinyl, aziridinyl, azocanyl, dihydropyridazinyl, dihydropyridinyl, dihydropyrimidinyl, morpholinyl, piperazinyl, piperidinyl, pyrrolidinyl, pyrrolinyl, dihydrothiazolyl, dihydropyridinyl, and thiomorpholinyl.
- non-nitrogen containing non-aromatic heterocycles include, but are not limited to, dioxanyl, dithianyl, tetrahydrofuryl, dihydropyranyl, tetrahydropyranyl, and [1,3]dioxolanyl.
- the heterocycles of the invention are substituted with hydrogen, or optionally substituted with 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9 substituents independently selected from acyl, acyloxy, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxyimino, alkoxysulfonyl, alkyl, alkylsulfonyl, amido, arylalkyl, arylalkoxycarbonyl, carboxy, cyano, formyl, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, mercapto, nitro, oxo, thioalkoxy, —NR A R B , and (NR A R B )sulfonyl.
- substituents independently selected from acyl, acyloxy, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl,
- heterocycles include, but are not limited to, azetidin-2-one, azepan-2-one, isoindolin-1,3-dione, (Z)-1H-benzo[e][1,4]diazepin-5(4H)-one, pyridazin-3(2H)-one, pyridin-2(1H)-one, pyrimidin-2(1H)-one, pyrimidin-2,4(1H,3H)-dione, pyrrolidin-2-one, benzo[d]thiazol-2(3H)-one, pyridin-4(1H)-one, imidazolidin-2-one, 1H-imidazol-2(3H)-one, piperidin-2-one, tetrahydropyrimidin-2(1H)-one, 1H-benzo[d]imidazol-2(3H)-one, [1,2,4]thiadiazolonyl, [1,2,5]thiadiazol
- room temperature refers to about 25° C.
- room temperature can vary within a few degrees depending on the environment in which any reaction is conducted. For example, temperatures from about 20° C. to about 30° C. are considered to be room temperature.
- R denotes a chiral center that can be designated as a R- or S-stereocenter.
- These stereoisomers are “R” or “S” depending on the configuration of substituents around the chiral carbon atom.
- R and S used herein are configurations as defined in the IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem., 1976, 45:13-30.
- chiral refers to a compound that is enantiopure or contains only one of a possible two configurations at a designated stereocenter.
- THF for tetrahydrofuran
- CDI 1,1′-carbonyldiimidazole
- NaH for sodium hydride
- NaHCO 3 for sodium bicarbonate
- MTBE for methyl t-butyl ether
- BH 3 for borane
- DMSO for dimethylsulfoxide
- EtOAc for ethyl acetate
- NaOtBu sodium t-butoxide
- OTf for trifluoromethanesulfonate.
- NLT is used to denote “Not Less Than”.
- the present invention relates to a process for preparing a chiral compound of formula:
- R 2 , R 3 , R 3a , R 3b are hydrogen;
- R 1 is a 5- to 6-membered heteroaryl ring, cyanophenyl, a 8- to 12-membered bicyclic heteroaryl ring, or a 4- to 12-membered heterocyclic ring; and
- R 4 and R 5 taken together with the nitrogen atom to which they are attached form an amine moiety represented by structure:
- R 7 , R 8 , R 9 , and R 10 at each occurrence are independently selected from the group consisting of hydrogen, hydroxyalkyl, fluoroalkyl, cycloalkyl, and alkyl;
- R 11 , R 12 , R 13 , and R 14 are each independently selected from the group consisting of hydrogen, hydroxyalkyl, alkyl, and fluoroalkyl;
- R x and R y are each independently selected from the group consisting of hydrogen, hydroxy, alkyl, alkoxy, alkylamino, fluoro, and dialkylamino;
- Q is O or S; and
- m is an integer from 1 to 5.
- enantiomerically pure arylcyclopropanecarboxylic acids salt can be broken-up to release the enantiomerically pure arylcyclopropanecarboxylic acids that can be further reacted with amines, reduced, and coupled with a suitable aromatic, heteroaromatic, or heterocycle group to provide compounds of formula (II).
- the chiral amine is selected from the group consisting of (S)-( ⁇ )- ⁇ -methylbenzylamine, (R)-(+)-N-benzyl- ⁇ -methylbenzylamine, (S)-( ⁇ )-N-benzyl- ⁇ -methylbenzylamine, (R)-(+)-N,N-dimethyl-1-phenylethylamine, (S)-( ⁇ )-N,N-dimethyl-1-phenylethylamine, [R—(R*,R*)]-(+)-bis(a-methylbenzyl)amine, [S—(R*,R*)]-( ⁇ )-bis(a-methylbenzyl)amine, (S)-(+)-1-cyclohexylethylamine, (R)-(+)-1-(1-naphthyl)ethylamine, (S)-( ⁇ )-1-(1-naphthyl)ethylamine, (1
- the chiral amine is (R)-( ⁇ )-1-cyclohexylethylamine. In another embodiment, the chiral amine is (R)-(+)-a-methylbenzylamine.
- the reaction is carried out in a polar organic solvent.
- the polar organic solvent is an alcohol.
- the alcohol can be selected from the group consisting of methanol, ethanol, isopropyl alcohol, tert-butyl alcohol, and n-butyl alcohol.
- the alcohol is isopropyl alcohol.
- the alcohol is tert-butyl alcohol.
- the reaction is carried at a temperature of from about room temperature to about 75° C.
- the temperature is from about 40° C. to about 60° C. In one particular embodiment, the temperature at which the reaction is carried out is from about 45° C. to about 50° C. Typically, the reaction is accomplished in a period of about 1 to 48 hours, however, the length of the reaction time can vary depending on the particular conditions and quality of the reagents, among other aspects of the reaction. In a preferred embodiment, the reaction is conducted for a time period of about 8 hours.
- the aryl-cyclopropanecarboxylic acid is prepared from arylaldehyde. An illustration of a process for preparing arylcyclopropanecarboxylic acid from aryl aldehyde is shown below in Scheme A.
- aryl aldehyde (A-1) is treated with t-butyldimethylphosphonoacetate to provide tert-butyl arylacrylate (A-2).
- Tert-butyl arylacrylate is treated a sulfoxonium ylide to provide tert-butyl arylcyclopropanecarboxylic acid ester (A-3).
- Hydrolysis of the tert-butyl arylcyclopropanecarboxylic acid ester under basic conditions with lithium hydroxide provides arylcyclopropanecarboxylic acid (A-4).
- aryl aldehyde (A-1) is treated with t-butyldimethylphosphonoacetate with any strong base in a non-polar solvent.
- the strong base is a metal hydride.
- metal hydride base are lithium hydride and sodium hydride.
- the strong base can also be potassium t-butyloxide, sodium t-butyloxide, lithium t-butyloxide.
- sodium hydride (NaH) is the base or potassium t-butyloxide. The reaction is carried out in any non-polar solvent.
- the non-polar solvent is an organic solvent, for example, toluene, hexane, benzene, 1,4-dioxane, chloroform, or diethyl ether.
- the organic solvent is toluene.
- Suitable sulfoxonium ylides for treating tert-butyl arylacrylate (A-2) to provide tert-butyl arylcyclopropanecarboxylic acid ester (A-3) can be dimethylsulfoxonium iodide methylide (Corey-Chaykovsky Regent) and trimethylsulfoxonium iodide reagent.
- the sulfoxonium reagent is trimethylsulfoxonium iodide reagent.
- the sulfoxonium reagent is dimethylsulfoxonium iodide methylide.
- the reaction is carried out in a polar solvent.
- the polar solvent can be any suitable polar aprotic solvent.
- Suitable polar aprotic solvents include, but are not limited to, dimethyl sulfoxide, dimethyl acetamide, dimethyl formamide, or mixtures thereof.
- the solvent is a mixture of dimethyl sulfoxide and dimethyl acetamide.
- the mixture can be in a ratio of from about 1:1 to about 2:1 dimethyl sulfoxide/dimethyl acetamide.
- the reaction can be carried out at any temperature, however, in the reaction mixture is maintained at a temperature of less than about 10° C.
- any base is suitable for use in the hydrolysis of the ester of tert-butyl arylcyclopropanecarboxylic acid (A-3) to provide arylcyclopropanecarboxylic acid (A-4).
- the base is any metal hydroxide base.
- Such base can include, for example, sodium hydroxide, lithium hydroxide, and potassium hydroxide.
- Suitable amine reagents can be represented by the formula:
- R 7 , R 8 , R 9 , and R 10 at each occurrence are independently selected from the group consisting of hydrogen, hydroxyalkyl, fluoroalkyl, cycloalkyl, and alkyl;
- R 11 , R 12 , R 13 , and R 14 are each independently selected from the group consisting of hydrogen, hydroxyalkyl, alkyl, and fluoroalkyl;
- R x and R y are each independently selected from the group consisting of hydrogen, hydroxy, alkyl, alkoxy, alkylamino, fluoro, and dialkylamino;
- Q is O or S; and
- m is an integer from 1 to 5.
- Suitable amines for the reaction can include any amine of formula (a), as defined above.
- Such amine can be more particularly selected from pyrrolidine, 2-(S)-methylpyrrolidine, 2-(R)-methylpyrrolidine, 3-methylpyrrolidine, 2-fluoropyrrolidine, 3-fluoropyrrolidine, 2-hydroxypyrrolidine, 3-hydroxypyrrolidine, 2-hydroxymethylpyrrolidine, and 3-hydroxymethylpyrrolidine.
- Other suitable amines can be more particularly selected from pyridine, 2-methylpyridine, 3-methylpyridine, 4-methylpyridine, 2-fluoropyridine, 3-fluoropyridine, 4-fluoropyridine, 2-hydroxypyridine, 3-hydroxypyridine, 4-hydroxymethylpyridine, 2-hydroxymethylpyridine, 3-hydroxymethylpyridine, and 4-hydroxymethylpyridine.
- the amines are those wherein one of the substituents represented by R 7 , R 8 , R 9 , and R 10 is hydrogen or alkyl and the other substituents are hydrogen.
- Particular preferred examples are pyrrolidine, 2-(S)-methylpyrrolidine, and 2-(R)-methylpyrrolidine.
- Suitable amines are those of formula (b), as defined above. Such amine may be more particularly selected from dimethylamine, diethylamine, methylamine, and ethylamine. In one particular embodiment, the amines are those wherein one of the substituents represented by R 7 , R 8 , R 9 , and R 10 is hydrogen or alkyl and the other substituents are hydrogen. Particular preferred examples are dimethylamine and diethylamine.
- Additional reagents having an amine group are those of formula (c), as defined above.
- Such amine may be more particularly selected from morpholine and thiomorpholine.
- the amine reagent is morpholine.
- the reaction is carried out using N,N′-carbonyldiimidazole.
- the arylcyclopropanecarboxylic acid, amine, and N,N′-carbonyldiimidazole are combined in an organic solvent.
- suitable organic solvents are tetrahydrofuran, toluene, 1,2-dimethoxyethane, 1,4-dioxane, N-methyl-pyrrolidinone, dimethylacetamide, and dimethylformamide.
- the solvent is tetrahydrofuran.
- the solvent is toluene. Tetrahydrofuran is the most preferred solvent.
- the reaction can be accomplished at room temperature.
- the reaction is accomplished in a period of about 1 to 48 hours, however, the length of the reaction time can vary depending on the particular conditions and quality of the reagents, among other aspects of the reaction. In a preferred embodiment, the reaction is conducted for a time period of about 8 hours.
- the cyclopropanecarboxylic acid amide is reduced using a reducing agent selected from borane reducing reagents.
- Suitable reducing agents are, for example, borane tetrahydrofuran complex, diborane, borane dimethylsulfide complex, a combination of sodium borohydride and sodium trifluoride.
- the reaction is conducted in a polar, aprotic solvent.
- suitable solvents are tetrahydrofuran, 1,2-dimethoxyethane, 1,2-diethoxyethane, 2-methyltetrahydrofuran, 1,4-dioxane, and methyl-tert-butyl ethers.
- the preferred solvent is tetrahydrofuran.
- the reaction can be conducted at any suitable temperature. Typically, the reaction is conducted at a temperature between 0° C. and 80° C. In a preferred embodiment, the reaction is conducted at a temperature of about 50° C. Typically, the reaction is accomplished in a period of about 1 to 48 hours, however, the length of the reaction time can vary depending on the particular conditions and quality of the reagents, among other aspects of the reaction. In one embodiment, the reaction is conducted for a time period of about 8 hours.
- the compound of formula (I-b) undergoes coupling reactions to provide the compounds of formula (II).
- Coupling conditions commonly referred to as metal-catalyzed reaction including palladium, nickel, iron or copper catalyzed reaction, such as Ullmann reaction conditions, are preferred for the reaction.
- Reagent suitable for providing a moiety within the definition of R 1 can be used.
- Reagents suitable for the reaction can include, for example, 5- to 6-membered heteroaryl, 8- to 12-membered bicyclic heteroaryl, and 4- to 12-membered heterocyclic reagents.
- Examples of particular 5- to 6-membered heteroaryl reagents include, but are not limited to, pyridazin-3(2H)-one, pyridin-2(1H)-one, pyrimidin-2(1H)-one, pyrimidin-2,4(1H,3H)-dione, pyrrolidin-2-one, benzo[d]thiazol-2(3H)-one, pyridin-4(1H)-one, pyrroline, imidazolidin-2-one, 1H-imidazol-2(3H)-one, piperidin-2-one, tetrahydropyrimidin-2(1H)-one, [1,2,4]thiadiazolone, [1,2,5]thiadiazolone, [1,3,4]thiadiazinone, [1,2,4]oxadiazolone, [1,2,5]oxadiazolone, and [1,3,4]oxadiazin-one.
- Examples of particular 4- to 12-membered heterocyclic reagents include, but are not limited to, azepane, azetidine, aziridine, azocane, dihydropyridine, dihydropyrimidine, piperidine, pyrrolidine, dihydrothiazole, dihydropyridine, thiomorpholine, dioxane, dithiane, tetrahydrofuran, dihydropyrane, tetrahydropyran, [1,3]dioxolane, azetidin-2-one, and azepan-2-one.
- Examples of particular 8- to 12-membered bicyclic heteroaryl reagents include, but are not limited to, isoindolin-1,3-dione, (Z)-1H-benzo[e][1,4]diazepin-5(4H)-one, and 1H-benzo[d]imidazol-2(3H)-one.
- the reaction is conducted with a copper catalyst and base in a polar aprotic solvent in the presence of N,N′-dimethylenediamine.
- the copper catalyst can be any copper catalyst.
- the copper catalyst is a copper (I) catalyst. Examples of such catalysts are, for example, copper (I) iodide, copper (I) bromide, and copper (I) chloride. Copper (I) iodide is preferred.
- the base is any suitable organic base.
- Examples of such base can include, for example, potassium carbonate (K 2 CO 3 ), potassium phosphate (K 3 PO 4 ), cesium carbonate (Cs 2 CO 3 ), sodium methoxide (NaOMe), sodium tert-butoxide (NaOt-Bu), sodium acetate (NaOAc), and potassium tert-butoxide (KOt-Bu).
- the base is K 2 CO 3 .
- the base is K 3 PO 4 .
- the basic solvent can be any polar aprotic solvent.
- polar aprotic solvent examples include, for example, dimethyl acetamide, dimethyl formamide, 1-methyl-2-pyrrolidinone, and pyridine.
- the polar aprotic solvent is pyridine.
- the reaction can be conducted at any suitable temperature. Typically, the reaction is conducted at a temperature between 0° C. and 140° C. In a preferred embodiment, the reaction is conducted at a temperature of about 115° C. Typically, the reaction is accomplished in a period of about 1 to 48 hours, however, the length of the reaction time can vary depending on the particular conditions and quality of the reagents, among other aspects of the reaction. In one embodiment, the reaction is conducted for a time period of about 8 hours.
- the present invention in one embodiment, also relates to compounds that are:
- the chiral amines are (S)-( ⁇ )- ⁇ -methylbenzylamine, (R)-(+)-N-benzyl-a-methylbenzylamine, (S)-( ⁇ )-N-benzyl- ⁇ -methylbenzylamine, (R)-(+)-N,N-dimethyl-1-phenylethylamine, (S)-( ⁇ )-N,N-dimethyl-1-phenylethylamine, [R—(R*,R*)]-(+)-bis( ⁇ -methylbenzyl)amine, [S-(R*,R*)]-( ⁇ )-bis(a-methylbenzyl)amine, (S)-(+)-1-cyclohexylethylamine, (R)-(+)-1-(1-naphthyl)ethylamine, (S)-( ⁇ )-1-(1-naphthyl)ethylamine, (1R,2R,3R
- the chiral amines also can be selected from (R)-( ⁇ )-1-cyclohexylethylamine or (R)-(+)- ⁇ -methylbenzylamine.
- the chiral amine is (R)-( ⁇ )-1-cyclohexylethylamine.
- the chiral amine is (R)-(+)- ⁇ -methylbenzylamine.
- the present invention also relates to compounds that are:
- the present invention in another embodiment, relates to a compound of formula:
- R 7 , R 8 , R 9 , and R 10 at each occurrence are independently selected from the group consisting of hydrogen, hydroxyalkyl, fluoroalkyl, cycloalkyl, and alkyl;
- R 11 , R 12 , R 13 , and R 14 are each independently selected from the group consisting of hydrogen, hydroxyalkyl, alkyl, and fluoroalkyl;
- R x and R y are each independently selected from the group consisting of hydrogen, hydroxy, alkyl, alkoxy, alkylamino, fluoro, and dialkylamino;
- Q is O or S; and
- m is an integer from 1 to 5.
- the present invention in another embodiment, relates to a compound of formula:
- R 7 , R 8 , R 9 , and R 10 at each occurrence are independently selected from the group consisting of hydrogen, hydroxyalkyl, fluoroalkyl, cycloalkyl, and alkyl;
- R 11 , R 12 , R 13 , and R 14 are each independently selected from the group consisting of hydrogen, hydroxyalkyl, alkyl, and fluoroalkyl;
- R x and R y are each independently selected from the group consisting of hydrogen, hydroxy, alkyl, alkoxy, alkylamino, fluoro, and dialkylamino;
- Q is O or S; and
- m is an integer from 1 to 5.
- the present invention also includes isotopically-labeled compounds, which are identical to those recited in Formula (I-a), (I-b), and (II), but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
- isotopes suitable for inclusion in the compounds of the invention are hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as but not limited to 2 H, 3 H, 13 C, 15 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 Cl, respectively.
- isotopes such as deuterium, i.e., 2 H
- Compounds incorporating positron-emitting isotopes are useful in medical imaging and positron-emitting tomography (PET) studies for determining the distribution of receptors.
- Suitable positron-emitting isotopes that can be incorporated in compounds of formula (I) are 11 C, 13 N, 15 O, and 18 F.
- Isotopically-labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art using appropriate isotopically-labeled reagent in place of non-isotopically-labeled reagent.
- compositions typically also comprise one or more conventional pharmaceutically acceptable carriers, adjuvants, and/or vehicles (together referred to as “excipients”).
- compositions for oral administration and solid dosage forms in particular, are preferred.
- Such solid dosage forms include, for example, capsules, tablets, pills, powders, and granules.
- the compounds or salts are ordinarily combined with one or more excipients.
- the compounds or salts can be mixed with, for example, lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted or encapsulated for convenient administration.
- Such capsules or tablets can contain a controlled-release formulation, as can be provided in, for example, a dispersion of the compound or salt in hydroxypropylmethyl cellulose.
- the dosage forms also can comprise buffering agents, such as sodium citrate, or magnesium or calcium carbonate or bicarbonate. Tablets and pills additionally can be prepared with enteric coatings.
- the compounds and compositions of the invention are useful for treating and preventing certain diseases and disorders in humans and animals.
- the compounds described in the invention can affect physiological processes in humans and animals.
- the compounds and compositions described in the invention are useful for treating and preventing diseases and disorders modulated by histamine-3 receptors.
- treatment or prevention of such diseases and disorders can be effected by selectively modulating the histamine-3 receptors in a mammal, by administering a compound or composition of the invention, either alone or in combination with another active agent as part of a therapeutic regimen.
- the compounds of the invention may be useful for the treatment and prevention of diseases or conditions such as attention-deficit hyperactivity disorder (ADHD), deficits in attention, dementia, and diseases with deficits of memory, learning, schizophrenia, cognitive deficits of schizophrenia, cognitive deficits and dysfunction in psychiatric disorders, Alzheimer's disease, mild cognitive impairment, epilepsy, seizures, allergic rhinitis, and asthma, motion sickness, dizziness, Meniere's disease, vestibular disorders, vertigo, obesity, diabetes, type II diabetes, Syndrome X, insulin resistance syndrome, metabolic syndrome, pain, including neuropathic pain, neuropathy, sleep disorders, narcolepsy, pathological sleepiness, jet lag, drug abuse, mood alteration, bipolar disorder, depression, obsessive compulsive disorder, Tourette's syndrome, Parkinson's disease, and medullary thyroid carcinoma, melanoma, and polycystic ovary
- ADHD attention-deficit hyperactivity disorder
- dementia dementia
- diseases with deficits of memory learning
- schizophrenia cognitive deficit
- the preferred total daily dose of a compound or salt is typically from about 0.001 to about 100 mg/kg, more preferably from about 0.001 to about 30 mg/kg, and even more preferably from about 0.01 to about 10 mg/kg (i.e., mg of the compound or salt per kg body weight).
- Dosage unit compositions can contain such amounts or submultiples thereof to make up the daily dose.
- the administration of the compound or salt will be repeated a plurality of times. Multiple doses per day typically may be used to increase the total daily dose, if desired.
- Factors affecting the preferred dosage regimen include the type, age, weight, sex, diet, and condition of the patient; the severity of the pathological condition; the severity of the pathological condition; pharmacological considerations, such as the activity, efficacy, pharmacokinetic, and toxicology profiles of the particular compound or salt used; whether a drug delivery system is utilized; and the specific drug combination.
- the dosage regimen actually employed can vary widely, and therefore, can derive from the preferred dosage regimen set forth above.
- the flask and wetcake were rinsed with the mother liquors, followed by isopropyl alcohol (5 mL).
- the wetcake was dried on the filter under vacuum (1.88 g, 61.5% ee).
- the wetcake was then charged back to the round-bottom flask with isopropyl alcohol (38 mL, 20 mL/g).
- the suspension was heated to 80° C. After 0.5 h, all solids dissolved.
- the solution was then slowly cooled to 50° C. ( ⁇ 2 h), during which time a suspension formed.
- the suspension was stirred at 50° C. for 2 h, and then slowly cooled to room temperature (1-2 h). Stirred the suspension overnight ( ⁇ 15 h) at room temperature.
- the suspension was filtered.
- the chiral salt 5 was first broken up by treating it with citric acid solution, exacted with MTBE and drying to obtain the free acid, 2-(4-bromophenyl)cyclopropanecarboxylic acid 4 (4.82 g, 20 mmol) and mixed with 1,1′-carbonyldiimidazole (4.22 g, 26 mmol) in THF (45 mL, 10 mL/g total volume). A suspension formed after stirring at room temperature for >30 min. The suspension was cooled to ⁇ 15° C. Then a solution of the (S)-2-methylpyrrolidine (2.55 g, 30 mmol) in THF (5 mL) was added over ⁇ 5 min.
- reaction of 5 (3.62 g, 15 mmol) with CDI (3.16 g, 19.5 mmol) and piperidine (2.22 mL, 22.5 mmol) afforded 6b in an assay yield of 4.55 g (14.8 mmol, 99% assay yield, 99% peak area).
- a sample was purified by washing the product solution with 5% NaHCO 3 and concentrating in vacuo to an oil that solidified at room temperature to provide the standard.
- reaction of 5 (3.62 g, 15 mmol) with CDI (3.16 g, 19.5 mmol) and diethylamine (2.33 mL, 22.5 mmol) afforded 6c in an assay yield of 4.18 g (14.1 mmol, 94% assay yield, 98% peak area).
- a sample was purified by washing the product solution with 5% NaHCO 3 and concentrating in vacuo to an oil to provide the standard.
- reaction of 5 (3.62 g, 15 mmol) with CDI (3.16 g, 19.5 mmol) and 2 M dimethylamine in THF (11.25 mL, 22.5 mmol) afforded 6d in an assay yield of 3.67 g (13.7 mmol, 91% assay yield, 99% peak area).
- a sample was purified by washing the product solution with 5% NaHCO 3 and concentrating in vacuo to an oil that solidified at room temperature to provide the standard.
- reaction of 5 (3.62 g, 15 mmol) with CDI (3.16 g, 19.5 mmol) and morpholine (1.96 mL, 22.5 mmol) afforded 6e in an assay yield of 4.48 g (14.45 mmol, 96% assay yield, 100% peak area).
- a sample was purified by washing the product solution with 5% NaHCO 3 and concentrating in vacuo to a white solid to provide the standard.
- reaction of 5 (3.62 g, 15 mmol) with CDI (3.16 g, 19.5 mmol) and pyrrolidine (1.86 mL, 22.5 mmol) afforded 6f in an assay yield of 4.24 g (14.40 mmol, 96% assay yield, 100% peak area).
- a sample was purified by washing the product solution with 5% NaHCO 3 and concentrating in vacuo to a white solid to provide the standard.
- reaction of 5 (3.62 g, 15 mmol) with CDI (3.16 g, 19.5 mmol) and (R)-2-methylpyrrolidine (1.92 g, 22.5 mmol) afforded 6 g in an assay yield of 4.62 g (15.00 mmol, 100% assay yield, 97.5% peak area).
- a sample was purified by washing the product solution with 5% NaHCO 3 and concentrating in vacuo to an oil that solidified at room temperature to provide the standard.
- the product solution is then cooled to room temperature and extracted with t-butyl methyl ether (40 mL, 2 ⁇ ).
- the basic aqueous layer is then extracted with more MTBE (40 mL).
- the organic layers are combined and washed with saturated sodium chloride solution (40 mL).
- the resulting product solution was assayed by HPLC against a known standard. 2.66 g product was assayed (92% assayed yield, >99% peak area).
- a sample was concentrated under high vacuum to an oil to provide a standard.
- reaction of 6b (3.70 g assayed, 12.0 mmol) with 1 M BH 3 in THF (42.0 mL, 42.0 mmol) afforded 7b in an assay yield of 2.77 g (9.4 mmol, 78% assay yield, 99% peak area).
- a sample was concentrated in vacuo to an oil to provide the standard.
- a sample was concentrated in vacuo to an oil to provide the standard.
- a sample was concentrated in vacuo to an oil to provide the standard.
- reaction of 6e (4.20 g assayed, 13.55 mmol) with 1 M BH 3 in THF (47.4 mL, 47.4 mmol) afforded 7e in an assay yield of 2.68 g (9.05 mmol, 67% assay yield, 100% peak area).
- a sample was concentrated in vacuo to an oil to provide the standard.
- a sample was concentrated in vacuo to an oil to provide the standard.
- a sample was concentrated in vacuo to an oil to provide the standard.
- the yield was increased by stepwise addition of isopropyl alcohol alternating with hold times over 10 h at 15° C., reducing the water content to 10% (by volume) in the final solvent composition.
- the solid was filtered and washed with isopropyl alcohol twice (4.5 mL/g free base). Wet cake was dried at 50° C. under vacuum, in humidified environment, with intermittent slight nitrogen bleeding. The isolated solid was used as a standard.
- reaction of 7b (2.67 g assayed, 9.08 mmol) with 3(2H)-pyridazinone (1.14 g, 11.8 mmol) afforded a solution of the free base of 8b in an assayed yield of 2.61 g (93% assay yield, 95% peak area).
- reaction of 7c (2.87 g assayed, 10.2 mmol) with 3(2H)-pyridazinone (1.27 g, 13.2 mmol) afforded a solution of the free base of 8c in an assayed yield of 2.55 g (84% assay yield, 93% peak area).
- reaction of 7d (2.13 g assayed, 8.37 mmol) with 3(2H)-pyridazinone (1.05 g, 10.5 mmol) afforded a solution of the free base of 8d in an assayed yield of 1.57 g (5.8 mmol, 70% assay yield, 93% peak area).
- reaction of 7f (3.05 g assayed, 10.90 mmol) with 3(211)-pyridazinone (1.36 g, 14.17 mmol) afforded a solution of the free base of 8f in an assayed yield of 3.60 g (74% assay yield, 97% peak area).
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Abstract
Description
wherein R1, R2, R3, R3a, R3b, R4, and R5 are as defined below. Compounds of formula (II) are described in WO 2007150010, published on Dec. 27, 2007, corresponding to U.S. patent application Ser. No. 11/766,987, filed on Jun. 22, 2007, and U.S. patent application Ser. No. 11/956,816, filed on Dec. 14, 2007, each of which are all hereby incorporated by reference. The present invention offers a more efficient process to obtain chiral compounds of formula (II) via the chiral resolution of an aryl-cyclopropanecarboxylic acid with chiral amines. The chiral resolution step forms a diasteriomeric chiral salt, which is crystallized to obtain an enantiomerically pure salt. The enantiomerically pure arylcyclopropyl carboxylic acid is obtained upon breaking up the salt. The resulting enantiomerically pure cyclopropyl carboxylic acids can be reacted with various amines to form amides, which can be reduced to form chiral amine derivatives. The intermediate chiral amines can be further coupled with a desired aromatic or heteroaromatic reagent to provide compounds of formula (II).
wherein R2, R3, R3a, R3b, are hydrogen; R1 is a 5- to 6-membered heteroaryl ring, cyanophenyl, a 8- to 12-membered bicyclic heteroaryl ring, or a 4- to 12-membered heterocyclic ring; and R4 and R5 taken together with the nitrogen atom to which they are attached form an amine moiety represented by structure:
wherein R7, R8, R9, and R10 at each occurrence are independently selected from the group consisting of hydrogen, hydroxyalkyl, fluoroalkyl, cycloalkyl, and alkyl; R11, R12, R13, and R14 are each independently selected from the group consisting of hydrogen, hydroxyalkyl, alkyl, and fluoroalkyl; Rx and Ry are each independently selected from the group consisting of hydrogen, hydroxy, alkyl, alkoxy, alkylamino, fluoro, and dialkylamino; Q is O or S; and m is an integer from 1 to 5.
A. Chiral Resolution of Cyclopropanecarboxylic Acid with Chiral Amines
is treated with a chiral amine to form a diasteromeric chiral salt, which can be further crystallized to form an enantiomerically pure salt. The enantiomerically pure arylcyclopropanecarboxylic acids salt can be broken-up to release the enantiomerically pure arylcyclopropanecarboxylic acids that can be further reacted with amines, reduced, and coupled with a suitable aromatic, heteroaromatic, or heterocycle group to provide compounds of formula (II). In one embodiment, the chiral amine is selected from the group consisting of (S)-(−)-α-methylbenzylamine, (R)-(+)-N-benzyl-α-methylbenzylamine, (S)-(−)-N-benzyl-α-methylbenzylamine, (R)-(+)-N,N-dimethyl-1-phenylethylamine, (S)-(−)-N,N-dimethyl-1-phenylethylamine, [R—(R*,R*)]-(+)-bis(a-methylbenzyl)amine, [S—(R*,R*)]-(−)-bis(a-methylbenzyl)amine, (S)-(+)-1-cyclohexylethylamine, (R)-(+)-1-(1-naphthyl)ethylamine, (S)-(−)-1-(1-naphthyl)ethylamine, (1R,2R,3R,5S)-(−)-isopinocamphenylamine, (1S,2S,3S,5R)-(+)-isopinocamphenylamine, (1R2R)-(−)-pseudoephedrine, (1S,2S)-(+)-pseudoephedrine, (1R,2S)-(−)-ephedrine, (1S,2R)-(+)-ephedrine, (1R,2S)-(−)-N-methylephedrine, (1S,2R)-(+)-N-methylephedrine, (1R,2S)-(−)-norephedrine, (1S,2R)-(+)-norephedrine, (1R,2S)-(+)-cis-1-amino-2-indanol, (1S,2R)-(−)-cis-1-amino-2-indanol, quinine, and cinchonine. In one embodiment, the chiral amine is (R)-(−)-1-cyclohexylethylamine. In another embodiment, the chiral amine is (R)-(+)-a-methylbenzylamine. In a preferred embodiment, the reaction is carried out in a polar organic solvent. In one embodiment the polar organic solvent is an alcohol. The alcohol can be selected from the group consisting of methanol, ethanol, isopropyl alcohol, tert-butyl alcohol, and n-butyl alcohol. In one embodiment, the alcohol is isopropyl alcohol. In another embodiment, the alcohol is tert-butyl alcohol. In one embodiment, the reaction is carried at a temperature of from about room temperature to about 75° C. In a particular embodiment, the temperature is from about 40° C. to about 60° C. In one particular embodiment, the temperature at which the reaction is carried out is from about 45° C. to about 50° C. Typically, the reaction is accomplished in a period of about 1 to 48 hours, however, the length of the reaction time can vary depending on the particular conditions and quality of the reagents, among other aspects of the reaction. In a preferred embodiment, the reaction is conducted for a time period of about 8 hours.
In another embodiment, the aryl-cyclopropanecarboxylic acid is prepared from arylaldehyde. An illustration of a process for preparing arylcyclopropanecarboxylic acid from aryl aldehyde is shown below in Scheme A.
obtained from the chiral resolution is coupled with an amine. An illustration of the process is shown below in Scheme 2.
wherein R7, R8, R9, and R10 at each occurrence are independently selected from the group consisting of hydrogen, hydroxyalkyl, fluoroalkyl, cycloalkyl, and alkyl; R11, R12, R13, and R14 are each independently selected from the group consisting of hydrogen, hydroxyalkyl, alkyl, and fluoroalkyl; Rx and Ry are each independently selected from the group consisting of hydrogen, hydroxy, alkyl, alkoxy, alkylamino, fluoro, and dialkylamino; Q is O or S; and m is an integer from 1 to 5.
is reacted with a suitable aromatic or non-aromatic reagent to provide compounds of formula (II). An illustration of this process is shown below in Scheme 4.
In a preferred embodiment, the compound of formula (I-b) undergoes coupling reactions to provide the compounds of formula (II). Coupling conditions, commonly referred to as metal-catalyzed reaction including palladium, nickel, iron or copper catalyzed reaction, such as Ullmann reaction conditions, are preferred for the reaction.
wherein, the chiral amines are (S)-(−)-α-methylbenzylamine, (R)-(+)-N-benzyl-a-methylbenzylamine, (S)-(−)-N-benzyl-α-methylbenzylamine, (R)-(+)-N,N-dimethyl-1-phenylethylamine, (S)-(−)-N,N-dimethyl-1-phenylethylamine, [R—(R*,R*)]-(+)-bis(α-methylbenzyl)amine, [S-(R*,R*)]-(−)-bis(a-methylbenzyl)amine, (S)-(+)-1-cyclohexylethylamine, (R)-(+)-1-(1-naphthyl)ethylamine, (S)-(−)-1-(1-naphthyl)ethylamine, (1R,2R,3R,5S)-(−)-isopinocamphenylamine, (1S,2S,3S,5R)-(+)-isopinocamphenylamine, (1R2R)-(−)-pseudoephedrine, (1S,2S)-(+)-pseudoephedrine, (1R,2S)-(−)-ephedrine, (1S,2R)-(+)-ephedrine, (1R,2S)-(−)-N-methylephedrine, (1S,2R)-(+)-N-methylephedrine, (1R,2S)-(−)-norephedrine, (1S,2R)-(+)-norephedrine, (1R,2S)-(+)-cis-1-amino-2-indanol, (1S,2R)-(−)-cis-1-amino-2-indanol, quinine, or cinchonine. The chiral amines also can be selected from (R)-(−)-1-cyclohexylethylamine or (R)-(+)-α-methylbenzylamine. In one embodiment, the chiral amine is (R)-(−)-1-cyclohexylethylamine. In another embodiment, the chiral amine is (R)-(+)-α-methylbenzylamine.
i.e. 2-(4-bromophenyl)cyclopropanecarboxylic acid R-(−)-1-cyclohexylethylamine salt and 2-(4-bromophenyl)cyclopropanecarboxylic acid (R)-(+)-α-methylbenzylamine salt.
wherein R7, R8, R9, and R10 at each occurrence are independently selected from the group consisting of hydrogen, hydroxyalkyl, fluoroalkyl, cycloalkyl, and alkyl; R11, R12, R13, and R14 are each independently selected from the group consisting of hydrogen, hydroxyalkyl, alkyl, and fluoroalkyl; Rx and Ry are each independently selected from the group consisting of hydrogen, hydroxy, alkyl, alkoxy, alkylamino, fluoro, and dialkylamino; Q is O or S; and m is an integer from 1 to 5.
wherein R7, R8, R9, and R10 at each occurrence are independently selected from the group consisting of hydrogen, hydroxyalkyl, fluoroalkyl, cycloalkyl, and alkyl; R11, R12, R13, and R14 are each independently selected from the group consisting of hydrogen, hydroxyalkyl, alkyl, and fluoroalkyl; Rx and Ry are each independently selected from the group consisting of hydrogen, hydroxy, alkyl, alkoxy, alkylamino, fluoro, and dialkylamino; Q is O or S; and m is an integer from 1 to 5.
F. Isotopically-Labeled Compounds
Claims (16)
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